Tobacco use is a major health problem. Although current therapies for smoking cessation have had some success, they are inadequate to help all smokers abstain from tobacco use. The reinforcing effects of numerous drugs of abuse, including nicotine, are partially modulated by dopaminergic neurotransmission (Koob and LeMoal, 1997;Di Chiara, 2000;Koob, 2000;Dani and De Biasi, 2001;Nestler, 2002). Cholinergic systems have repeatedly been shown to modulate dopamine release (Dani and Di Biasi, 2001;Kaneko et al., 2000), which act through release of ACh that activates nicotinic acetylcholine receptors (nAChRs). Nicotine exerts its actions through these same receptors. The goals of this project are to assess a number of compounds that are agonists and/or antagonists of nAChRs for their selectivity at various subtypes of nAChRs that modulate dopaminergic activity. Therefore, the primary targets of our efforts are the various subtypes of presynaptic nAChRs in dopaminergic terminal fields. The nAChR population on dopaminergic terminals is quite heterogeneous and includes a substantial fraction that are sensitive to inhibition by a-conotoxin MM (a-CtxMII) that have been shown to be a6[unreadable]2*-nAChR (the * indicates other subunits may be incorporated, see Lukas et al., 1999 for nAChR nomenclature). This class of nAChR has a very limited distribution in the CNS and somewhat unique pharmacology. It is possible that a selective agonist or antagonist for this class of receptors, alone or in combination with an agonist or antagonist of the a4[unreadable]2*-nAChR found on GABAergic neurons, could be of use as a therapy for smoking cessation. We intend to screen the test compounds systematically in tissues that naturally express the nAChR of interest using a hierarchical approach as indicated by the following four Specific Aims.